US6384186B2 - Cyclic dodecapeptide and process for the preparation thereof - Google Patents

Cyclic dodecapeptide and process for the preparation thereof Download PDF

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US6384186B2
US6384186B2 US09/077,489 US7748998A US6384186B2 US 6384186 B2 US6384186 B2 US 6384186B2 US 7748998 A US7748998 A US 7748998A US 6384186 B2 US6384186 B2 US 6384186B2
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omphalotus
omphalotin
pests
omphalotus olearius
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US20010008634A1 (en
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Heidrun Anke
Winfried Etzel
Wolfgang Gau
Rüdiger Hain
Michael Kilian
Anke Mayer
Olov Sterner
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Bayer AG
Vattenfall AB
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the novel omphalotin can be employed for controlling pests and parasites in plants and warm-blooded animals.
  • it has high activity against nematodes and arthropods (like insects and arachnids), and against microbial pests, in particular against fungi and bacteria.
  • the novel compound and compositions comprising this compound can be employed particularly advantageously in crop protection, in the protection of stored products, in the hygiene sector and in animal breeding and animal husbandry.
  • the novel compound of the formula (I) is obtained by cultivating suitable microorganisms from the class of the Basidiomycetes, preferably from the genera Omphalotus and Lampteromyces, particularly preferably Omphalotus, in a customary manner in a cultured medium containing assimilable carbon and nitrogen sources and mineral salts, under aerobic conditions, and isolating the desired compound by customary methods.
  • omphalotus strains in particular Omphalotus olearius strains (synonym: Clitocybe illudens strains).
  • Omphalotus olearius strains No. 83 039, 90 173, 91 050, 92 095, 93 162 and 90 170 and those variants and mutants of these strains which have features which are essential for carrying out the present invention, or which have the same function.
  • FIG. 1 is a table indicating the 1 H NMR spectra data for a compound according to the invention
  • FIG. 2 is another table indicating the 1 H NMR spectra data for a compound according to the invention.
  • Omphalotus olearius strains are novel. They have been deposited at the Deutschen Sammlung von Mikroorganismen und Zellkullturen GmbH (DSM), Mascheroder Weg 1b, D 38124 Braunschweig, Federal Republic of Germany, in accordance with the provisions of the Treaty of Budapest on the international recognition of the deposition of microorganisms for the purpose of patent processes and have the following deposition numbers or entry numbers:
  • the proton signals of the individual amino acids are assigned starting from the NH, or the ⁇ proton, by means of the H-H couplings.
  • the HMQC spectrum it is then possible to assign the carbon signals in a similar manner.
  • the sequence of the amino acids was determined with the aid of the NOESY and the HMBC spectrum.
  • NOESY spectrum the spatial distance of the NH of an amino acid to the ⁇ proton(s) of the next amino acid is detected.
  • the ⁇ protons of two amino acids which are linked to each other are correlated to the same carbonyl carbon.
  • the ⁇ protons also show two correlation peaks to carbonyl carbons: one peak by two-bond coupling to the carbonyl carbon of its own amino acid and one peak by three-bond coupling to the carbonyl carbon of the N-linked amino acid.
  • the structure of the novel compound according to the invention was determined by extensive analytical, in particular spectroscopic, studies. However, since errors in the interpretation of the analytical data of substances of complex structure cannot always be totally excluded, omphalotin is additionally described by some characteristic physico-chemical data and spectra.
  • the novel omphalotin is produced by the fermentation of suitable strains of microorganisms from the class of the Basidiomycetes, in particular of the orders Omphalotus and Lampteromyces, preferably Omphalotus olearius (synonym: Clitocybe illudens) and very particularly preferably of the Omphalotus olearius strains 83 039 (DSM 9737), 90 173 (DSM 9738), 91 050 (DSM 9739), 92 095 (DSM 9740), 93 162 (DSM 9741) or 90 170 (DSM 9742) or by mutants or variants thereof.
  • suitable strains of microorganisms from the class of the Basidiomycetes, in particular of the orders Omphalotus and Lampteromyces, preferably Omphalotus olearius (synonym: Clitocybe illudens) and very particularly preferably of the Omphalotus olearius
  • the culture media are inoculated by customary methods, for example using oblique tubes or flask cultures.
  • the cultivation can be carried out in all culture media which are known to be used for the cultivation of microorganisms of the class of the Basidiomycetes.
  • the culture medium must contain one or more assimilable carbon sources and nitrogen sources and mineral salts, it being possible for these products to be present in the form of defined individual components, or else in the form of complex mixtures, as represented in particular by biological products of diverse origin.
  • Suitable carbon sources are all customary carbon sources.
  • Examples include carbohydrates, in particular polysaccharides, such as starch or dextrins, disaccharides, such as maltose or cane sugar, monosaccharides such as glucose or xylose, sugar alcohols such as mannitol or glycerol and naturally occurring mixtures such as malt extract, molasses or whey powder.
  • Suitable nitrogen sources are all customary organic and inorganic nitrogen sources.
  • Examples include proteins, protein hydrolysates, amino acids such as glutamic acid, aspartic acid, arginine, lysine, ornithine or serine, nucleoside bases such as cytosine or uracil and soya bean meal, cotton seed meal, lentil meal, pea meal, soluble and insoluble plant proteins, maize steep liquor, yeast extract, peptones and meat extract and also ammonium salts and nitrates, for example NH 4 Cl, (NH 4 ) 2 SO 4 , NaNO 3 and KNO 3 .
  • the mineral salts which should be present in the culture medium generate, for example, the following ions:
  • the culture media can vary within wide ranges. The kind and the composition of the culture media will generally depend on which components are in each case available at particularly low cost. In general, the culture solutions contain preferably about 0.5 to 8%, in particular 0.6 to 6%, of carbon sources, preferably about 0.5 to 4%, in particular 0.5 to 2%, of nitrogen sources and preferably about 0.001 to 0.5%, in particular 0.003 to 0.3%, of mineral salts.
  • the amount of the compound according to the invention which becomes enriched in the cultivation broth generally reaches its maximum after about 1 to 10, preferably about 4 to 7, days after the beginning of the cultivation.
  • the desired end product of fermentation can be determined with the aid of thin-layer-chromatographical studies, with the aid of HPLC and UV absorption spectra, in the plate diffusion test using a suitable fungus as test strain, or by the nematicidal or insecticidal activity.
  • the usual precautions are taken, such as sterilization of the culture media, of the culture vessels and of the air required for aeration.
  • sterilization of the equipment it is for example possible to use both steam and dry sterilization, the temperatures preferably being at 100 to 140° C., in particular at 120 to 130° C.
  • the customary chemical defoamers for example liquid fats and oils, oil-water emulsions, paraffins, higher alcohols, such as octadecanol, silicone oils, polyoxyethylene or polyoxypropylene compounds (for example in amounts of up to about 1%) may be added. Foam may also be reduced or eliminated with the aid of the customary mechanical devices (which use, for example, centrifugal forces).
  • the compound according to the invention can be isolated by customary physico-chemical methods from the culture medium and from the biomass.
  • the isolation may be carried out for example by the customary extraction processes, precipitation processes and/or chromatographic processes.
  • the final purification of the isolated substance may also be carried out with the aid of the abovementioned methods. However, in many cases a final purification is not necessary, since minor impurities which may be present do not adversely affect the activity of the compound.
  • customary physico-chemical methods for example measuring of a characteristic band in the spectrum or of the R f values, determination of the antimicrobial or of the nematicidal and insecticidal activity, etc., may be employed to find the fractions in which the compound according to the invention is present in the highest concentration or purity. These methods can also be employed to find suitable microorganisms by routine processes.
  • culture filtrate and mycel are separated by customary methods (for example centrifugation).
  • the compound according to the invention can be isolated, and, if appropriate, purified, from the culture filtrate, preferably from the biomass, with the aid of customary extraction processes, precipitation processes and/or chromatographic processes. Chromatography can be carried out in the form of column chromatography.
  • Suitable for use as adsorbents are the customary inorganic or organic adsorbents, such as, for example, alumina, silica gel, magnesium silicate, activated charcoal, cellulose, cellulose derivatives, synthetic resins such as polyamides, for example acetylated polyamide, dextran gels or modified dextran gels.
  • Suitable for use as eluents are all the different solvents or solvent mixtures in which the compound according to the invention is soluble. Preference is given to using water, ammonia solution, chloroform and methanol or mixtures thereof (for example mixtures of chloroform, methanol and aqueous NH 3 or methanol and water).
  • chromatographic processes for example non-specific adsorption on sorbents such as silica gel, ion exchange chromatography or gel diffusion chromatography. These are methods which are known from the purification of water-soluble charged natural compounds.
  • the compound according to the invention can be obtained from its solutions by customary methods, for example by the evaporation of the solvent, freeze-drying, etc.
  • the biomass (the mycel) is obtained by centrifugation of the fermentation material (culture broth and mycel) which is obtained by the aerobic cultivation of the strains at about 27° C.
  • the novel substance is preferably obtained by extraction of the biomass. It can also be isolated from the culture filtrate by adsorption on activated charcoal or on suitable resins.
  • the most economical method has been proven to be the binding of the substance according to the invention to unspecific adsorber resins based on polystyrene (for example Amberlite XAD or Lewatit OC 1031).
  • Desorption of the compounds according to the invention is carried out fractionally, by mixtures of water and organic solvents, in particular water/methanol. The fractions which show activity in the test against Meloidogyne incognita are concentrated under reduced pressure until the organic solvent has been completely removed and, if appropriate, lyophilized.
  • the lyophilized crude product is taken up in water and, after insoluble components have been separated off, purified further by customary chromatographic processes.
  • the novel substance is finally prepared in pure form by customary chromatographic methods, preferably by silica gel chromatography or preparative HPLC.
  • the compound according to the invention is suitable for controlling animal pests, in particular insects, arachnids and nematodes, encountered in agriculture, in forests, in the protection of stored products and of materials, and in the hygiene sector. It is preferably used as a crop protection agent. It is active against normally sensitive and resistant species and against all or some stages of development.
  • the abovementioned pests include:
  • Isopoda for example, Oniscus asellus, Armadillidium vulgare and Porcellio scaber.
  • Chilopoda for example, Geophilus carpophagus and Scutigera spec.
  • Symphyla for example, Scutigerella immaculata.
  • Thysanura for example, Lepisma saccharina.
  • Orthoptera for example, Blatta orientalis, Periplaneta americana, Leucophaea maderae, Blattella germanica, Acheta domesticus , Gryllotalpa spp., Locusta migratoria migratorioides, Melanoplus differentialis and Schistocerca gregaria.
  • Thysanoptera From the order of the Thysanoptera, for example, Hercinothrips femoralis and Thrips tabaci.
  • From the order of the Homoptera for example, Aleurodes brassicae, Bemisia tabaci, Trialeurodes vaporariorum, Aphis gossypii, Brevicoryne brassicae, Cryptomyzus ribis, Aphis fabae, Aphis pomi, Eriosoma lanigerum, Hyalopterus arundinis, Phylloxera vastatrix , Pemphigus spp., Macrosiphum avenae , Myzus spp., Phorodon humuli, Rhopalosiphum padi , Empoasca spp., Euscelis bilobatus, Nephotettix cincticeps, Lecanium corni, Saissetia oleae, Laodelphax striatellus, Nilaparvata lugens, Aonidiella aurantii, Aspidiotus hederae ,
  • Hymenoptera From the order of the Hymenoptera, for example, Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis and Vespa spp.
  • Acarina for example, Acarus siro , Argas spp., Ornithodoros spp., Dermanyssus gallinae, Eriophyes ribis, Phyllocoptruta oleivora , Boophilus spp., Rhipicephalus spp., Amblyomma spp., Hyalomma spp., Ixodes spp., Psoroptes spp., Chorioptes spp., Sarcoptes spp., Tarsonemus spp., Bryobia praetiosa , Panonychus spp. and Tetranychus spp.
  • the phytoparasitic nematodes include, for example, Pratylenchus spp., Radopholus similis, Ditylenchus dipsaci, Tylenchulus semipenetrans , Heterodera spp., Globodera spp., Meloidogyne spp., Aphelenchoides spp., Longidorus spp., Xiphinema spp. and Trichodorus spp.
  • Microbial pests which can be controlled with the aid of the novel compound include in particular the phytopathogenic fungi:
  • Plasmodiophoromycetes Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes.
  • Phytopathogenic bacteria include in particular Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
  • Xanthomonas species such as, for example, Xanthomonas campestris pv. oryzae ; Pseudomonas species, such as, for example, Pseudomonas syringae pv. lachrymans ; Erwinia species, such as, for example, Erwinia amylovora ; Pythium species, such as, for example, Pythium ultimum ; Phytophora species, such as, for example, Phytophthora infestans;
  • Pseudoperonospora species such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubense ; Plasmopara species, such as, for example, Plasmopara viticola ; Peronospora species, such as, for example, Peronospora pisi or P. brassicae;
  • Erysiphe species such as, for example, Erysiphe graminis ; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea ; Podosphaera species, such as, for example, Podosphaera leucotricha ; Venturia species, such as, for example, Venturia inaequalis ; Pyrenophora species, such as, for example, Pyrenophora teres or P. graminea (conidia form: Drechslera, syn: Helminthosporium);
  • Cochliobolus species such as, for example, Cochliobolus sativus (conidia form: Drechslera, syn: Helminthosporium); Uromyces species, such as, for example, Uromyces appendiculatus ; Puccinia species, such as, for example, Puccinia recondita ; Tilletia species, such as, for example, Tilletia caries ; Ustilago species, such as, for example, Ustilago nuda or Ustilago avenae ; Pellicularia species, such as, for example, Pellicularia sasakii ; Pyricularia species, such as, for example, Pyricularia oryzae ; Fusarium species, such as, for example, Fusarium culmorum;
  • Botrytis species such as, for example, Botrytis cinerea ; Septoria species, such as, for example, Septoria nodorum; Leptosphaeria species, such as, for example, Leptosphaeria nodorum ; Cercospora species, such as, for example, Cercospora canescens ; Alternaria species, such as, for example, Alternaria brassicae ; and Pseudocercosporella species, such as, for example, Pseudocercosporella herpotrichoides .
  • Helminthosporium carbonum may be mentioned.
  • the compound of the formula (I) according to the invention in particular has outstanding nematicidal activity, for example against Meloidogyne incognita.
  • the active compound can be converted to the customary formulations, such as solutions, emulsions, wettable powders, suspensions, powders, dusting agents, pastes, soluble powders, granules, suspo-emulsion concentrates, natural and synthetic materials impregnated with active compound and very fine capsules in polymeric substances.
  • customary formulations such as solutions, emulsions, wettable powders, suspensions, powders, dusting agents, pastes, soluble powders, granules, suspo-emulsion concentrates, natural and synthetic materials impregnated with active compound and very fine capsules in polymeric substances.
  • formulations are produced in a known manner, for example by mixing the active compound with extenders, that is liquid solvents and/or solid carriers, if appropriate with the use of surfactants, that is emulsifiers and/or dispersants and/or foam-formers.
  • Suitable liquid solvents are essentially: aromatics, such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons, for example mineral oil fractions, mineral and vegetable oils, alcohols, such as butanol or glycol and their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethyl sulphoxide and water.
  • aromatics such as xylene, toluene or alkylnaphthalenes
  • chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride
  • aliphatic hydrocarbons for example mineral oil fractions,
  • Suitable solid carriers are:
  • suitable solid carriers for granules are: for example crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and synthetic granules of inorganic and organic meals, and granules of organic material such as sawdust, coconut shells, maize cobs and tobacco stalks;
  • suitable emulsifiers and/or foam-formers are: for example nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates as well as protein hydrolysates; suitable
  • Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, and natural phospholipids, such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations.
  • Other additives can be mineral and vegetable oils.
  • colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs
  • trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • the formulations in general contain between 0.1 and 95 per cent by weight of active compound, preferably between 0.5 and 90%.
  • the active compound according to the invention can be present in its commercially available formulations and in the use forms, prepared from these formulations, as a mixture with other active compounds, such as insecticides, attractants, sterilizing agents, bactericides, acaricides, nematicides, fungicides, growth-regulating substances or herbicides.
  • active compounds such as insecticides, attractants, sterilizing agents, bactericides, acaricides, nematicides, fungicides, growth-regulating substances or herbicides.
  • the insecticides include, for example, phosphates, carbamates, carboxylates, chlorinated hydrocarbons, phenylureas and substances produced by microorganisms, inter alia.
  • bronopol dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations.
  • a mixture with other known active compounds, such as herbicides, or with fertilizers and growth-regulators is also possible.
  • the active compound according to the invention can furthermore be present in its commercially available formulations and in the use forms, prepared from these formulations, as a mixture with synergists.
  • Synergists are compounds which increase the action of the active compounds, without it being necessary for the synergist added to be active itself.
  • the active compound content of the use forms prepared from the commercially available formulations can vary within wide limits.
  • the active compound concentration of the use forms can be from 0.0000001 to 95% by weight of active compound, preferably between 0.0001 and 1% by weight.
  • the compound is employed in a customary manner appropriate for the use forms.
  • the active compound can be applied to above-ground parts of plants, or via the soil. Treatment of seed is also possible.
  • the active compound When used against hygiene and stored-product pests, the active compound has an excellent residual action on wood and clay and a good stability to alkali on limed substrates.
  • the active compound is suitable for controlling pathogenic endoparasites which occur in humans and in particular in animal keeping and animal breeding, in productive animals, breeding animals, zoo animals, laboratory animals, animals for experimentation and pets. They are active against all or individual stages of development of the pests and against resistant and normally sensitive species.
  • pathogenic endoparasites include cestodes, trematodes, nematodes and Acantocephalea, in particular:
  • Pseudophyllidea e.g.: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.
  • Cyclophyllidea e.g.: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomasa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
  • Ascaridia spp. From the order of the Ascaridia e.g.: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
  • Spirurida e.g.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
  • Filariida e.g.: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.
  • the productive and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer and reindeer, furbearing animals such as mink, chinchilla and raccoon, birds such as chicken, geese, turkeys and ducks, fresh- and salt-water fish such as trout, carp and eels, reptiles, insects such as honey-bee and silkworm.
  • Laboratory and experimental animals include mice, rats, guinea-pigs, golden hamsters, dogs and cats.
  • Administration can be carried out both prophylactically and therapeutically.
  • Enteral administration of the active compound is carried out, for example, orally in the form of powders, tablets, capsules, pastes, drinks, granules, orally administrable solutions, suspensions and emulsions, boluses, medicated feed or drinking water.
  • Dermal administration is carried out, for example, in the form of dipping, spraying or pouring-on and spotting-on.
  • Parenteral administration is carried out, for example, in the form of injections (intramuscular, subcutaneous, intravenous, intraperitoneal), or by implants.
  • Suitable preparations are:
  • solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pouring-on formulations, gels;
  • Solubilizers which may be mentioned are: solvents which promote the dissolution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan ester.
  • Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid esters, n-butanol.
  • Oral solutions are administered directly. Concentrates are administered orally after prior dilution to the use concentration. Oral solutions and concentrates are prepared as described above for the solutions for injection, sterile procedures not being necessary.
  • Solutions for use on the skin are trickled on, spread on, rubbed in, sprinkled on or sprayed on. These solutions are prepared as described above for the solutions for injection.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal silicic acid, aluminium monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtures. If appropriate, other auxiliaries such as colorants, bioabsorption-promoting substances, antioxidants, light stabilizers, adhesives are added.
  • Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone and 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.
  • aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol
  • esters such as ethyl acetate, butyl acetate
  • Colorants are all colorants permitted for use on animals and which can be dissolved or suspended.
  • Absorption-promoting substances are, for example, DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
  • Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol.
  • Light stabilizers are, for example, novantisolic acid.
  • Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
  • Emulsions can be administered orally, dermally or as injections.
  • Emulsions are either of the water-in-oil type or of the oil-in-water type.
  • Hydrophobic phases which may be mentioned are: liquid paraffins, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic/capric biglyceride, triglyceride mixture with vegetable fatty acids of the chain length C 8-12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids possibly also containing hydroxyl groups, mono- and diglycerides of the C 8 /C 10 fatty acids.
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol perlargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C 16 -C 18 , isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C 12 -C 18 , isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as synthetic duck coccygeal gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, inter alia.
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
  • Fatty acids such as oleic acid and its mixtures.
  • Hydrophilic phases which may be mentioned are:
  • alcohols such as propylene glycol, glycerol, sorbitol and its mixtures.
  • Emulsifiers which may be mentioned are: non-ionic surfactants, e.g. polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
  • non-ionic surfactants e.g. polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
  • ampholytic surfactants such as di-Na N-lauryl- ⁇ -iminodipropionate or lecithin;
  • anionic surfactants such as Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt.
  • auxiliaries which may be mentioned are: substances which enhance the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the substances mentioned.
  • substances which enhance the viscosity and stabilize the emulsion such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of the substances mentioned.
  • Suspensions can be administered orally, dermally or as injection. They are prepared by suspending the active compound in a suspending agent, if appropriate with addition of other auxiliaries such as wetting agents, colorants, bioabsorption-promoting substances, preservatives, antioxidants, light stabilizers.
  • auxiliaries such as wetting agents, colorants, bioabsorption-promoting substances, preservatives, antioxidants, light stabilizers.
  • Liquid excipients which may be mentioned are all homogeneous solvents and solvent mixtures.
  • wetting agents which may be mentioned are the surfactants given above.
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only by their higher viscosity.
  • the active compound is mixed with suitable excipients, if appropriate with addition of auxiliaries, and brought into the desired form.
  • Excipients which may be mentioned are all physiologically tolerable solid inert substances. Those used are inorganic and organic substances. Inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, hydrogencarbonates, aluminium oxides, silicic acids, argillaceous earths, precipitated or colloidal silica, phosphates.
  • Organic substances are, for example, sugar, cellulose, foodstuffs and feeds such as milk powder, animal meal, grain meals and shreds, starches.
  • Auxiliaries are preservatives, antioxidants, colorants which have already been mentioned above.
  • auxiliaries are lubricants and glidants such as magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances such as starch or crosslinked polyvinylpyrrolidone, binders such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
  • lubricants and glidants such as magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances such as starch or crosslinked polyvinylpyrrolidone, binders such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
  • the active compounds can also be present in the preparations as a mixture with synergists or with other active compounds which act against pathogenic endoparasites.
  • Such active compounds are, for example, L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates, praziquantel, pyrantel, epsiprantel.
  • Ready-to-use preparations contain the active compound in concentrations of 10 ppm-20 per cent by weight, preferably of 0.1-10 per cent by weight.
  • Preparations which are diluted before use contain the active compound in concentrations of 0.5-90% by weight, preferably of 5-50% by weight.
  • test methods given in the examples are also particularly suitable to determine the omphalotin-containing fractions in the production of omphalotin. They can also be employed to estimate the particular omphalotin content.
  • the solution With continuous stirring, the solution is cooled to a temperature of about 50 to 60° C. 20 ml of the solution are transferred into 90 mm Petri dishes under sterile conditions. After the solution has cooled, the filled Petri dishes can be stirred at room temperature for a maximum of 8 weeks prior to an inoculation.
  • the agar of a solid media agar plate which is densely colonized by Omphalotus olearius (in the present example No. 90 170) is divided under sterile conditions into pieces of a size of 1 ⁇ 1 cm with the aid of a scalpel.
  • one agar mycel piece is transferred with a pair of tweezers onto a solid media agar plate as described under 1.1 (mycel facing upwards) and incubated in an incubation cabinet (Heraeus, type BK 5060 E) at 27° C. in the dark for a maximum of 3 weeks.
  • the colonized plates can be used as inoculation plates for the fermentation, or they can be used once more for the inoculation of solid media agar plates.
  • the total volume of the homogenized liquid is distributed evenly, using a 10 ml pipette (Becton Dickinson and Company, type Falcon), over the Erlenmeyer flask which had been prepared for inoculation.
  • the incubation of the preculture flasks is carried out in a shaking cabinet (Braun Melsungen type BS 4) at a temperature of 27° C. and a shaking speed of 120 rpm for 5 days.
  • a 42 l prefermenter (Braun Mels Institute type Biostat P) is filled with 30 l of demineralized water, and
  • the fermenter is closed and the content is sterilized at a temperature of 121° C. for 30 minutes.
  • an overpressure of 0.3 bar is applied and the aeration rate is set to 0.25 vvm.
  • the pO 2 meter is calibrated to an initial value of 99%.
  • the prefermenter is inoculated with 600 ml of the preculture prepared under 1.4.
  • two 1 l Erlenmeyer flasks, each containing 300 ml of preculture, are transferred under sterile conditions into a 2 l glass bottle (Schott) (the bottle is connected to a Braun Melsungen inoculating apparatus via a silicone tube).
  • the prefermenter is inoculated with the preculture under sterile conditions through a membrane in the lid.
  • Fermentation conditions Temperature 27° C. Stirrer speed 200 rpm Aeration rate 0.25 vvm Pressure 0.3 bar pH not controlled Antifoam as required Incubation time about 120 h, or at the most up to the point where the glucose concentration has decreased to c(glucose) ⁇ 1 g/l.
  • a 450 1 fermenter (Braun Melsungen type Biostat 450 D) is filled with 320 l of demineralized water, and
  • the fermenter is closed and the content is sterilized at a temperature of 121° C. for 30 minutes.
  • an overpressure of 0.3 bar is applied and the aeration rate is set to 0.25 vvm.
  • the pO 2 meter is calibrated to an initial value of 99%.
  • the main fermenter is inoculated with the content of the prefermenter via sterile transfer tubing.
  • the glucose concentration is determined using a Beckmann glucose analyser.
  • the fermentation in the 450 l fermenter is terminated and the biomass is harvested.
  • the content of the main fermenter is separated from the culture medium through gauze (Holthaus Medical, Verbandmull, Remscheid 11, Germany).
  • the biomass filtercake is washed repeatedly with demineralized water and subsequently centrifuged in a tumble drier (Miele, type MZ 5942, Germany) at 4000 rpm for 3 minutes. 3 to 6 kg of moist biomass are harvested.
  • the Omphalotus olearius biomass obtained is frozen at a temperature of ⁇ 34° C. and stored until further work-up.
  • the omphalotin was found in elements E 48-87. The content of the elements was removed and combined. 2 l of water were added, the mixture was shaken and the upper phase was separated off. The lower phase was extracted 3 times with 1 l of ethyl acetate p.a. each time. The combined upper phases were then extracted 4 times with 0.5 l of water each time, and the solvent was distilled off under reduced pressure using a rotary evaporator. The yield of the concentrated crude extract that remained was 135 mg. Further purification was carried out as in Example 2.3.
  • Jasco PU-980 fitted with high pressure pump LG-980-02 gradient mixer and multiwavelength detector MD-910 (Gross-Umstadt, Germany)
  • HPLC 1090 having a diode array detector, Hewlett Packard (Waldbronn, Germany)
  • Amount injected 10 ⁇ l of a 0.1% strength solution (per cent by weight) of the sample in acetonitrile
  • Test nematode Heterodera schachtii
  • the efficacy of the test substance is 100% if all test nematodes have been killed, and it is 0% if the number of nematodes that are still alive is the same as in the control.
  • Nematicidal activity of omphalotin ( ⁇ g/ml) Nematode LD 90 LD 50 Meloidogyne incognita 1-1.5 0.75
  • Test nematode Meloidogyne incognita
  • the efficacy of the test substance is 100% if no galls have been formed, and it is 0% if the same number of galls has been formed as in the control.
  • Test nematode Meloidogyne incognita
  • the efficacy of the test substance is 100% if no galls have been formed, and it is 0% if the same number of galls has been formed as in the control.
  • Efficacy in % Abbott
  • Control methanol 0 Omphalotin 5 ppm 61
  • the substance is dissolved in methanol. Dilutions are then prepared and pipetted into the wells of a multiwell tissue culture plate (24 well). The methanol is then allowed to evaporate in a fume cupboard, and 0.8 ml of physiological sodium chloride solution is filled into the wells. 100 nematodes in 0.2 ml of water are added in each case by means of a pipette.
  • the efficacy is 100% if all the nematodes have been killed. If the same number of nematodes are alive as in the control sample, the efficacy is 0%.
  • Test insect Plutella xylosella
  • test substance is dissolved in methanol and diluted to the test concentration using emulsifier-containing water (0.4 ml of emulsifier W/l of H 2 O).
  • emulsifier-containing water 0.4 ml of emulsifier W/l of H 2 O.
  • the leaf discs are dipped into the solutions of the test substances by means of a pair of tweezers and subsequently placed in Petri dishes (diameter 9 cm) lined with filter paper (1 leaf disc/Petri dish). Each leaf disc is infected with 6 L3 larvae. Visual scoring is carried out after two, six and 16 days. On the third and, if appropriate, on the sixth day of the treatment, the food is replenished with untreated leaf discs.
  • the efficacy of the test substance is 100% if all test insects have been killed, and it is 0% if the same number of insects are still alive as in the control.
  • Test method Petri dishes are prepared using 10 ml of potato dextrose agar. The test substance is applied as a solution to the agar and spread with the spatula until the solution has been soaked up by the culture medium. The inoculum of the microorganisms to be tested, as spores or mycel fragments, is stamped onto the agar plates by pressing a stamp, which is, if appropriate, covered with felt, first onto a densely overgrown plate and then onto the test plate. After 5 to 6 days, the radial growth of the microorganism colonies is measured and compared to that of the untreated control.
  • the efficacy of the test substance is 100% if no growth is detected, and it is 0% if growth is identical to that of the control.

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Cited By (12)

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US20020193594A1 (en) * 2001-03-28 2002-12-19 Joachim Rudolph Process for the preparation of carboxamides
US6982315B2 (en) * 2001-03-28 2006-01-03 Bayer Aktiengesellschaft Process for the preparation of carboxamides
US8822193B2 (en) 2010-02-25 2014-09-02 Marrone Bio Innovations, Inc. Isolated bacterial strain of the genus Burkholderia and pesticidal metabolites therefrom
US9433218B2 (en) 2010-02-25 2016-09-06 Marrone Bio Innovations, Inc. Isolated bacterial strain of the genus Burkholderia and pesticidal metabolites therefrom
US9526251B2 (en) 2010-02-25 2016-12-27 Marrone Bio Innovations, Inc. Use of Burkholderia formulations, compositions and compounds to modulate crop yield and/or corn rootworm infestation
US10149480B2 (en) 2010-02-25 2018-12-11 Marrone Bio Innovations, Inc. Use of Burkholderia formulations, compositions and compounds to modulate crop yield and/or corn rootworm infestation
US10159250B2 (en) 2010-02-25 2018-12-25 Marrone Bio Innovations, Inc. Isolated bacterial strain of the genus burkholderia and pesticidal metabolites therefrom
US11172684B2 (en) 2010-02-25 2021-11-16 Marrone Bio Innovations, Inc. Use of Burkholderia formulations, compositions and compounds to modulate crop yield and/or corn rootworm infestation
US11382331B2 (en) 2010-02-25 2022-07-12 Marrone Bio Innovations, Inc. Isolated bacterial strain of the genus Burkholderia and pesticidal metabolites therefrom
US11793201B2 (en) 2010-02-25 2023-10-24 Pro Farm Group, Inc. Isolated bacterial strain of the genus Burkholderia and pesticidal metabolites therefrom
US11917999B2 (en) 2010-02-25 2024-03-05 Pro Farm Group, Inc. Use of Burkholderia formulations, compositions and compounds to modulate crop yield and/or corn rootworm infestation
US9119401B2 (en) 2012-10-19 2015-09-01 Marrone Bio Innovations, Inc. Plant glutamine synthetase inhibitors and methods for their identification

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